Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax.
Aging is associated with lymphopenia and progressive decline in T cell functions; however, the mechanisms underlying these defects are unclear. We analyzed the expression of genes promoting apoptosis (fas/fasL1 and bax) and those inhibiting apoptosis (bcl-2 and bcl-xL) in lymphocytes from aging and young subjects at the protein level, using flow cytometry/Western blotting, and at the mRNA level, using quantitative PCR. Susceptibility of T cell subsets to undergo anti-Fas-induced apoptosis was analyzed by propidium iodide staining, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay, DNA fragmentation assay, and staining with Hoechst 33342 dye. An increased expression of Fas and Fas ligand and a decreased expression of Bcl-2 were observed in both CD4+ and CD8+ T cells from aging as compared with young controls. Increased Fas and decreased Bcl-2 expression were also found in memory cells of both CD4+ and CD8+ T cell subsets from aging. Bax expression was increased in lymphocytes from aging at both the protein and mRNA level. No significant difference was observed in Bcl-xL expression between aging and young; however, the ratio of Bax:Bcl-xL was increased in aging. An increased proportion of CD4+ and CD8+ T cell subsets from aging underwent apoptosis following anti-Fas Ab treatment as compared with CD4+ and CD8+ T cell subsets from young controls. These data suggest that increased apoptosis may be one of the mechanisms responsible for lymphopenia and T cell deficiency associated with human aging.
Aggarwal
S
S
Basic and Clinical Immunology, University of California, Irvine 92697, USA.
Gupta
S
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000096:biosynthesis* / Q000276:immunology
D000911:Antibodies, Monoclonal; C494826:BAX protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor